tbuckley/cabot-search huggingface dataset:
Medical student readiness to treat LGBTQ patients.
Authors: Matthew B. Schabath, Hannah C Karpel, Amani Sampson, Mia Charifson, Lydia Fein, Devin Murphy, Megan Sutter, Christina Tamargo, Gwendolyn Quinn
Journal: Journal of Clinical Oncology (2022)

11030 Background: The lesbian, gay, bisexual, transgender and queer (LGBTQ) community experiences cancer health disparities. It is thus imperative that medical trainees receive training in the care of LGBTQ populations. Identifying gaps in trainees’ knowledge and comfort in providing care for this population is important in preparing future physicians. Methods: A Likert-scale survey of US medical students at three institutions assessed attitudes, comfort and knowledge in providing care for LGBTQ patients. Results were quantified with descriptive and stratified analyses. Exploratory factor analysis found four factors in which attitude summary measure (ASM) scores were calculated; lower values indicate more agreeability with given attitude items. Total knowledge scores were calculated with higher values indicating greater knowledge. Results: Of 300 medical students who completed the survey, the majority were female (55.7%), white (54.7%), and heterosexual (64.3%). The majority of students felt comfortable (strongly agree/agree) participating in the care of patients who identify as lesbian (94.3%), gay (96.0%), and bisexual (96.3%); this percentage dropped to 82.3% for non-binary and 71.3% for transgender patients. Only 27.0% of students reported confidence in their knowledge of health needs of transgender patients. LGBTQ self-identification, percent of core rotations completed, and having LGBTQ friends/family were significantly associated with various ASM subscales (Table 1). Knowledge questions had high percentages of “neutral” responses, and students who identified as LGBTQ had significantly higher total knowledge scores. Conclusions: Overall, medical students feel comfortable and willing to provide care for LGBTQ patients. However, as in our prior study in oncologists, there is limited knowledge about specific LGBTQ health and cancer needs. More education and training in the needs of transgender and non-binary patients is indicated. [Table: see text]
ETMR-04. Embryonal tumor with multi-layered rosettes (ETMR) located in the brainstem: a case report on clinical decision-making and a multimodal, interdisciplinary treatment approach including interstitial brachytherapy
Authors: Stephanie T Jünger, Daniel Rueß, Roland Goldbrunner, Gerrit H Gielen, Torsten Peitsch, Pascal Johann, Pablo Landgraf, Thorsten Simon, Maximilian I Ruge
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE: Embryonal tumors with multi-layered rosettes (ETMR) (CNS WHO grade 4) comprise a rare and malignant tumor type affecting predominantly infants below 3 years of age. The treatment consists of maximal safe surgical resection, irradiation, and intensive medulloblastoma type chemotherapy. Despite aggressive treatment, the prognosis of these patients remains poor, especially for brainstem tumors. We present the case of a male infant diagnosed with a brainstem ETMR, successfully treated with an interdisciplinary multimodal approach, including stereotactic interstitial brachytherapy. RESULTS: A 19 month old boy first presented with hemiparesis, intermittent bradycardia and reduced consciousness. Initial imaging showed a brainstem lesion with characteristic features of a diffuse intrinsic pontine glioma (DIPG). We performed stereotactic biopsy to confirm the diagnosis and initiated temozolomide treatment. While the pathology result was still pending, the boy’s clinical condition deteriorated to a soporic state with stretch synergisms. By emergency open surgery, partial resection was achieved. Eventually, the patient recovered rapidly. After the diagnosis of ETMR was established, medulloblastoma type chemotherapy (systemic carboplatin/etoposide; intrathecal methotrexate) was administered. After two cycles, the patient showed only residual right-sided hemiparesis. However, imaging demonstrated only a minimal reduction of the tumor size. Therefore, stereotactic interstitial brachytherapy using 125iodine seeds and subsequent high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) was performed and overall tolerated well. After two months of brachytherapy and two additional cycles of chemotherapy, the MRI showed ≥ 50% reduction in tumor volume and no neurological deficit can be clinically detected. CONCLUSION: This case indicates that stereotactic interstitial brachytherapy during intensive systemic chemotherapy is feasible. It may provide a suitable treatment for malignant infant brain tumors. Furthermore, it shows that paediatric patients are capable of recovery even after devastating neurological symptoms. Lastly, it emphasizes the importance of multidisciplinary and multimodal treatment for rare diseases.
Large and Small Animal Models of Heart Failure With Reduced Ejection Fraction
Authors: Patrick M. Pilz, Jennifer E. Ward, Wei-Ting Chang, Attila Kiss, Edward Bateh, Alokkumar Jha, Sudeshna Fisch, Bruno K. Podesser, Ronglih Liao
Journal: Circulation Research (2022)

Heart failure (HF) describes a heterogenous complex spectrum of pathological conditions that results in structural and functional remodeling leading to subsequent impairment of cardiac function, including either systolic dysfunction, diastolic dysfunction, or both. Several factors chronically lead to HF, including cardiac volume and pressure overload that may result from hypertension, valvular lesions, acute, or chronic ischemic injuries. Major forms of HF include hypertrophic, dilated, and restrictive cardiomyopathy. The severity of cardiomyopathy can be impacted by other comorbidities such as diabetes or obesity and external stress factors. Age is another major contributor, and the number of patients with HF is rising worldwide in part due to an increase in the aged population. HF can occur with reduced ejection fraction (HF with reduced ejection fraction), that is, the overall cardiac function is compromised, and typically the left ventricular ejection fraction is lower than 40%. In some cases of HF, the ejection fraction is preserved (HF with preserved ejection fraction). Animal models play a critical role in facilitating the understanding of molecular mechanisms of how hearts fail. This review aims to summarize and describe the strengths, limitations, and outcomes of both small and large animal models of HF with reduced ejection fraction that are currently used in basic and translational research. The driving defect is a failure of the heart to adequately supply the tissues with blood due to impaired filling or pumping. An accurate model of HF with reduced ejection fraction would encompass the symptoms (fatigue, dyspnea, exercise intolerance, and edema) along with the pathology (collagen fibrosis, ventricular hypertrophy) and ultimately exhibit a decrease in cardiac output. Although countless experimental studies have been published, no model completely recapitulates the full human disease. Therefore, it is critical to evaluate the strength and weakness of each animal model to allow better selection of what animal models to use to address the scientific question proposed.
A bivalent Tim-3/PD-1 bispecific antibody for the treatment of PD-1 antibody resistant or refractory NSCLC.
Authors: Jiajian Liu, Y. Luan, H. Deng, F. Wang, C. Wang, Z. Zhang
Journal: Journal of Clinical Oncology (2022)

e14597 Background: Immune checkpoint inhibitors (ICI) PD-1/PD-L1 antibody are key drugs for the treatment of non-small cell lung cancer (NSCLC). Bispecific antibody is one of the strategies aimed at the clinical needs for NSCLC patients who are resistant to or refractory from ICI treatment. Tim-3, one of the next generation of ICB targets, is co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and Tim-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit. Methods: A bivalent to both Tim-3 and PD-1 bispecific antibody (Bis5) was developed and is in Phase I clinical trials for NSCLC patients who are resistant to or refractory from PD-1 antibody treatment. Results: Bis5 showed affinity of 5-8 nM to both Tim-3 and PD-1. Moreover, Bis5 showed better cell activity than Tim-3 and PD-1 antibody combination to activated T cell as well as NK and DC. Bis5 showed 77%-88% tumor inhibition which is close to PD-1 antibody alone in MC38 model. Neither PD-1 antibody or PD-1 and Tim-3 antibody combination show any activity in CT26 model while Bis5 showed significant tumor inhibition activity and doubled the survival rate. The highest non-severe toxicity dose (HNSTD) was 200mpk in monkeys. ADA were 33.3% (2/6), 83.3% (5/6), and 0.0% (0/6) at doses of 2, 10, and 50 mpk, respectively. The T1/2 were 31.7-66.5 h for doses 2-50 mpk. Conclusions: A Phase I, multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of Bis5 in patients with advanced and/or metastatic solid tumors has started. Seven cohorts (0.1, 0.3, 1, 3, 6, 10, 15 mg/kg) are planned to be enrolled sequentially in the dose escalation part. In the expansion part, a cohort group of 10 patients is planned for post PD-1 treated NSCLC as the second or third line treatment.
ATRT-22. Outcomes for children with recurrent atypical teratoid rhabdoid tumor: A single institution study with updated molecular and germline analysis
Authors: Steven S Carey, Jie Huang, Jason R Myers, Roya Mostafavi, Brent Orr, Layna H Michalik, Paul Klimo, Frederick Boop, Kim E Nichols, Thomas Merchant, David W Ellison, Giles W Robinson, Arzu Onar-Thomas, Amar Gajjar, Santhosh Upadhyaya
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Children with recurrent atypical teratoid rhabdoid tumor (recATRT) who fail frontline therapies have dismal outcomes. The association of ATRT molecular groups (SHH, TYR and MYC) and presence of underlying cancer predisposition with survival post-recurrence (postRD) is unknown. METHODS: We previously reported outcomes from a single-institution retrospective study of children &amp;lt;21 years with recATRT treated at St. Jude Children’s Research Hospital from 2000 to 2020. Herein we report updated progression-free survival (PFS2: time from initial recurrence to subsequent first progression) and overall survival (OSpostRD: time from initial recurrence to death/last follow-up) outcomes by molecular groups determined by tumor DNA methylation and by germline SMARCB1/SMARCA4 alterations (GLA). RESULTS: Median age and time from initial diagnosis to recurrence for 64 eligible patients were 2.1 years (range: 0.5-17.9 years) and 5.4 months (range: 0.5–125.6 months), respectively. The 2- and 5-year PFS2 and OSpostRD were 3.1% (±1.8%)/1.6% (±1.1%) and 20.3% (±4.8%)/7.9% (±3.8%), respectively. PFS2 did not differ by molecular groups (p=0.210) for 42 participants with available data (MYC=11, SHH=21, TYR=10). Children with TYR group had a better 2-year OSpostRD [60.0% ±14.3% (TYR) vs. 18.2% ±9.5% (MYC) or 4.8% ±3.3% (SHH)] (p=0.018). In univariate analyses, OSpostRD was also better with older age at diagnosis (≥ 1 year vs &amp;lt;1 year; p=0.03), female gender (p=0.008), and metastatic site of recurrence compared to local or combined sites of disease (p&amp;lt;0.001). OSpostRD did not differ for those with positive GLA (n=12) compared to those without (n=21) (p=0.231). Only 6 children (9.4%) (TYR=4, SHH=1, NA=1) were alive at median follow-up of 7.7 years from recurrence. CONCLUSION: Children with recATRT have extremely poor outcomes. Older age at diagnosis, female gender, TYR group, and metastatic site of initial recurrence were associated with longer survival in our study. These results reinforce the dire need for better therapeutic options.
Nested set information derived from fusion genes in Ewing sarcoma and other cancers.
Authors: Peter Meade Anderson, Luisa-Marie Manning, Brian Rubin, Timothy A. Chan, Scott E. Kilpatrick, Rabi Hanna, Zheng Jin Tu
Journal: Journal of Clinical Oncology (2022)

e23521 Background: Ewing family tumors including Ewing sarcoma (ES) and desmoplastic small round cell tumor (DSRCT) are characterized by EWSR1 and ETS fusion partners including EWS-FLI1, EWS-ERG, EWS-WT1, and others. Since 2019 our Next Generation Sequencing (NGS) sarcoma panel (N = 338) identified both fusion partners and exons containing the EWS breakpoint in ES and DSRCT. Hence, it should be possible to learn more about the exact breakpoints of EWS fusion genes. The molecular diversity and functionality of these fusion transcripts, especially the exact sequence, which could be identical, similar, or unique, may have significant biological implications for diagnostics and treatment options. We have used in-frame analysis of EWS gene fusion breakpoints to identify corresponding polypeptides spanning the breakpoints of the most common EWS gene fusions to provide useful insights about ES and DSRCT. Methods: Pathology reports and EWS gene fusions were analyzed using the Cleveland Clinic NGS panel which is based on anchored multiplex polymerase chain reaction (PCR) enriched for 34 gene targets. The amplicons were subjected to massively parallel sequencing with 151x2 cycle pair-end reads. An informatics pipeline was used for read alignment (GRCh37 as reference genome), fusion identification, and annotation. The DNA sequence across fusion junction and translational amino acid sequences were extracted for comparison in a preliminary teaching set (37/338 EWS fusions). Results: EWS-FLI1 fusions at exon 7-7 (chr22:29683123-chr11:128675261) and exon 7-6 (chr22:29683123-chr11:128651853) were the most common fusion genes in ES (N = 24/32;75%). Other ES gene fusions included exons 10-6, 7-10, 9-8, 7-2 EWS-FEV, 7-8 EWS-ERG, 7-9 EWS-ERG, and 10-9 EWS-ERG. EWS-WT1 gene fusions (chr22:29683123-chr11:32414301) in DSRCT exon 7-7 occurred in 4 of 5 cases (80%). In frame analysis of the common gene fusions in 75% of ES and DSRCT (total n = 37) yielded identical corresponding polypeptides that span the breakpoint (table). Conclusions: Analysis of ES and DSRCT fusion genes provides evidence that cancer-specific fusion genes are associated with common identical breakpoints and corresponding in-frame polypeptides. Our results show that the identification of in-frame polypeptides from the fusion gene sequencing can identify potential nested sets of cancer-specific mRNAs and polypeptides. This information may become relevant for diagnostic and therapeutic targets future vaccines and diagnostics against ES and DSRCT as well as other cancers characterized by fusion genes or frameshift mutations. [Table: see text]
Progression and mortality post-immunotherapy discontinuation among patients with BRAFV600-mutant (BRAF+) metastatic melanoma.
Authors: Sunandana Chandra, Evan Thomas Hall, You-Li Ling, Jackson Tang, Rohan Shah, Thach-Giao Truong
Journal: Journal of Clinical Oncology (2022)

9531 Background: Immunotherapy (IO) is commonly used to treat BRAF+ metastatic melanoma (MM) patients in the first line (1L) setting and has demonstrated durable outcomes in clinical trials. However, most patients discontinue IO therapy for toxicity, disease progression, or other reasons. To date, no multi-center or nationwide US-based study has examined treatment patterns and outcomes for patients with BRAF+ MM post discontinuation of 1L IO. The aim of this study is to describe real-world treatment patterns and outcomes among patients who discontinued 1L IO. Methods: This retrospective cohort study used the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) database, the harmonized customized data from Flatiron and ConcertAI. Patients were ≥18 years old, had a diagnosis of BRAF+ MM, were treated with pembrolizumab, nivolumab, or ipilimumab + nivolumab on or after 9/1/2014, and then discontinued 1L therapy. Reason for discontinuation was extracted from medical records. Descriptive statistics were used to describe baseline characteristics and treatment patterns. Kaplan–Meier curves were used to analyze time to progression or death (TTPD) and time to death (TTD). Results: Of the 898 included patients (mean age: 61 years; male: 65%); 46% initiated ipilimumab + nivolumab, 24% nivolumab, and 30% pembrolizumab. The most common reasons for 1L discontinuation were toxicity (26%) and progression (25%). Medical records noted 5.3% completed therapy on discontinuation and 34.5% provided no reason of discontinuation with median duration of therapy (MDOT) of 379 and 138 days respectively. At 6 months, 34 % (n = 303) remain on IL IO. MDOT for patients who discontinued IO due to toxicity and those who discontinued due to progression were 54 and 63.5 days respectively. Patients who discontinued due to toxicity had a median time of 142 days to next treatment. TTPD was best for patients who discontinued therapy due to completion or toxicity (6-month progression rate: 13% and 20%). Patients who discontinued due to progression did especially poorly (6-month progression rate: 59%). About 33% of patients (n = 296) needed second line (2L) therapy, and the majority (80.7%) received combination BRAF+ targeted therapy. Overall, 38% and 50% of patients died post IO discontinuation for any reason at 1 and 2 years, respectively. 31% of patients had brain metastases and a greater proportion (56%) died within a 2-year period compared with those without brain metastases (56% vs 49%, p = 0.0036). Conclusions: IO, although effective, is not curative for all patients. A significant number of patients discontinue therapy due to progression. Patients with BRAF+ MM who progress early on 1L IO therapy have a high risk of death and should be considered for other therapy options, including targeted therapy.
T-cell redirected bispecific antibodies in relapsed and refractory multiple myeloma: A systematic review and meta-analysis.
Authors: Syed Hamza Bin Waqar, Razwana Khanam, Mohammad Ebad Ur Rehman, Asmi Chattaraj, Hassam Ali, Faiz Anwer
Journal: Journal of Clinical Oncology (2022)

e20014 Background: Multiple myeloma (MM) is a malignant plasma cell disorder which remains incurable, and in relapsed and refractory treatment, chimeric antigen receptor therapy shows promise. Bispecific antibodies (bsAbs) utilize the exact mechanism by engaging BCMA and other potential tumor-associated antigens on myeloma cells and T-cells. We have conducted a systematic review and meta-analysis to evaluate the efficacy and safety of bsAbs in heavily pretreated MM cohorts. Methods: We searched PubMed, Clinicaltrials.gov, Cochrane, Google Scholar, Embase, and major conferences (oral and poster presentation), with MeSH terms and keywords for “multiple myeloma” or “relapsed refractory multiple myeloma,” AND “bispecific antibody” or “BiTE”. We included all original studies reported in the English language published from inception until January 2022. After primary and secondary screening, eleven clinical trials were included. Pooled analysis was done with the help of random effects model (Freeman-Tukey Double Arcsine Transformation) in OpenMetaAnalyst software. Results: We identified nine phase I and two phase II trials (n=837), with a mean age of 64.5 years. Most cohorts being triple-, quad- or penta-refractory MM. Complete response (CR) or stringent CR (sCR) reported is 12% (95% CI 9-15.3%, I² 16.54%, n=66), very good partial response (VGPR) 14.8% (95% CI 8.3-22.7%, I² 80.57%, n=93) and partial response (PR) 11.8% (95% CI 0.2-3.41%, I² 93.21%, n=26). The overall response rate (ORR) reported is 59.5% (95% CI 44.7-73.5%, I² 90.71%, n=307). Among the most common adverse events anemia is seen in 44.2% (95% CI 38.1-50.4%, I² 17.86%, n=152), neutropenia in 33.8% (95% CI 18.4-51.2%, I² 93.27%, n=179), thrombocytopenia in 32% (95% CI 21.4-43.6%, I² 75.96%, n=113) and cytokine release syndrome in 57.1% (95% CI 45.5-68.4%, I² 85.63%, n=315). Conclusions: Bispecific antibodies have shown promising efficacy in relapsed and refractory MM cohorts with a very well safety profile. Upcoming phase II/III trials are much awaited, along with combination studies of bsAbs with other agents to gauge response.[Table: see text]
Impact of resistance to cisplatin and osimertinib on dissemination properties of penile cancer cells
Authors: A. Thomas, S. Huck, K.S. Slade, O. Vakhrusheva, M. Michaelis, J.J. Cinatl, J. Cinatl, F. Rothweiler, A. Haferkamp, E. Juengel, I. Tsaur
Journal: European Urology (2022)
Preferential PDE4B Inhibition — A Step toward a New Treatment for Idiopathic Pulmonary Fibrosis
Authors: Rachel C Chambers
Journal: New England Journal of Medicine (2022)

Fibrosis, defined as the pathologic accumulation of extracellular matrix, is the final outcome of several common chronic inflammatory, immune-mediated, and metabolic diseases and accounts for up to 45% of all deaths in the industrialized world.1 The approval of pirfenidone and nintedanib for the treatment of idiopathic pulmonary fibrosis (IPF), a rapidly progressive and fatal fibrotic condition, represented a defining moment for the development of antifibrotic therapeutic agents.2,3 However, although these agents slow the decline in lung function, they do not halt disease progression, so IPF continues to represent a disease of high unmet clinical need. In this issue of the . . .
Effect of 18F-DCFPyL PET/CT (=PSMA PET) on the management of patients with suspected limited residual/recurrent disease following radical prostatectomy: Results of a prospective, multicenter registry trial
Authors: J. Chin, U. Metser, K. Zukotynski, V. Mak, D. Langer, P. Maccrostie, A. Finelli, A. Kapoor, L. Lavallee, L. Klotz, M. Hagerty, C. Hildebrand, G. Bauman
Journal: European Urology (2022)